Lysosomal Acid Lipase Deficiency (LAL-D)

Kanuma® (sebelipase alfa) is the only drug approved by the US Food and Drug Administration (FDA) for the treatment of patients with lysosomal acid lipase deficiency (LAL-D). Patients with LAL-D have a missing or faulty lysosomal acid lipase (LAL) enzyme. LAL plays an important role in breaking down fatty material in the lysosomes. Kanuma replaces LAL enzymes that are not working properly or missing with functioning LAL enzymes.

The recommended dose of Kanuma for adult and pediatric patients with rapidly progressive LAL-D is 1 mg/kg of body weight administered weekly via intravenous infusion. Healthcare providers can increase the dosage weekly up to 3 mg/kg of body weight for infants who do not respond to the initial dose. The infusion may take up to 2 hours depending on the healthcare provider, who might increase or decrease the infusion time. Patients usually receive infusions in a hospital, clinic, or specialized infusion center. Patients should get all infusions that are recommended by their healthcare provider.1

Clinical Pharmacology

Kanuma is a recombinant human lysosomal acid lipase (rhLAL) produced by recombinant DNA technology in the egg whites of eggs laid by genetically engineered chickens. It is a lysosomal glycoprotein enzyme that catalyzes the hydrolysis of triglycerides to free fatty acids and glycerol and the hydrolysis of cholesteryl ester to fatty acids and free cholesterol.

Kanuma has a molecular mass of approximately 55,000 daltons. It is a monomeric glycoprotein that contains 6 N-linked glycosylation sites. The amino acid sequence for Kanuma is the same as the amino acid sequence for human LAL. The specific activity of Kanuma varies between 195 and 345 units/mg. Under specified assay conditions, 1 unit of enzyme activity catalyzes the hydrolysis of 1 micromole of the synthetic substrate 4-methylumbelliferyl oleate per minute at 37 °C.

Therapeutic Efficacy

LAL-D is an autosomal recessive lysosomal storage disorder characterized by a genetic defect. Patients with LAL-D have a decrease or loss in activity of LAL. They experience a lysosomal accumulation of triglycerides and cholesterol in multiple organs, such as the intestines, liver, and spleen, as well as in the walls of blood vessels. This can occur due to deficient LAL enzyme activity leading to progressive complications.

The normal activity of LAL causes the breakdown of lipid particles, including low-density lipoprotein (LDL) cholesterol, and the primary site of action is the lysosome. Kanuma restores deficient LAL enzymes in patients with LAL-D.2  

The efficacy of Kanuma was evaluated in an open-label, multinational, single-arm phase 2/3 study, LAL-CL03, also referred to as VITAL. The results of the study were reported in preliminary forms. The study included infants with LAL-D confirmed by genetic tests or reduced enzyme activity who experienced growth failure or rapidly progressive disease within the first 6 months of life. The median age of the study patients was 3 months, and their ages ranged from 1.1 to 5.8 months old. All participants in the study displayed elevated levels of alanine aminotransferase (ALT) (median, 145 U/L) and aspartate aminotransferase (AST) (median, 125 U/L) at baseline with significant liver dysfunction. 

Patients received 0.2 mg/kg or 0.35 mg/kg of Kanuma once a week for the first 2 weeks, and then 1 mg/kg weekly. All patients in the study underwent dose escalation to 3 mg/kg once a week between 4 and 88 weeks of treatment due to suboptimal clinical response. The median treatment period was 11 weeks. One patient in the study underwent a dose increase to 5 mg/kg once weekly at week 88. Kanuma led to a substantial improvement in survival and clinically improved multiple disease activity parameters in infants with early-onset LAL-D beyond 1 and 2 years of age.3

Phase 2 Open-Label Clinical Trial

A phase 2 open-label extension study showed that Kanuma was well tolerated and that it rapidly reduced serum transaminases and improved lipid profiles in adult patients with LAL-D. It was the first adult human study with Kanuma. 

Patients with serum transaminase levels above the upper limit of normal experienced normalization of serum transaminase levels, which were sustained throughout the duration of the study. Transient increases in AST and ALT were occasionally observed in individual patients. Reductions in fat content and liver volume were also maintained, with improvement in the lipid profiles of patients in the study. 

The effect of Kanuma on the accumulation of lipid substrates in the spleen was not conclusive due to the low baseline spleen fat content of the patients. The patients did not demonstrate a clinical progression of LAL-D during Kanuma treatment.

The study also noted that treatment with Kanuma was well tolerated for 5 years. No patients discontinued treatment due to treatment emergent adverse events (TEAE). In terms of severity, TEAEs ranged from mild to moderate. Kanuma treatment was associated with low to moderate infusion-associated reactions (IAR). Kanuma addressed the underlying pathophysiology of LAL-D and effectively replaced the missing LAL enzyme.4  

Safety Assessments, Warnings, and Precautions

Safety assessments for Kanuma involved evaluation of vital signs, physical examination results, laboratory results, TEAEs, serious adverse effects, IARs, and anti-drug antibody (ADA) titers. All adverse events were coded using the Medical Dictionary of Regulatory Activities. Clinical laboratory tests were analyzed by local laboratories in the VITAL study. Patients with positive ADA titers were tested for the presence of positive antibodies; these antibodies inhibit sebelipase alfa enzyme activity and/or cellular uptake. The functional effects of the identified sequence changes were assessed using MutationTaster and PolyPhen-2 (polymorphism phenotyping) tools.5 Previous clinical studies showed that Kanuma can lead to hypersensitivity signs and symptoms in patients with LAL-D. Side effects experinced by patients treated with Kanuma included fever, chills, abdominal pain, agitation, edema, hypertension, irritability, laryngeal edema, eczema, pallor, rash, pruritus, vomiting, and nausea.²

Get full prescribing information for Kanuma at MPR.


  1. Your guide to infusions with Kanuma (sebelipase alfa). Alexion Pharmaceuticals, Inc. Accessed August 19, 2021.
  2. Kanuma. Package insert. Alexion Pharmaceuticals, Inc.; 2015. Accessed August 19, 2021.
  3. Frampton JE. Sebelipase alfa: a review in lysosomal acid lipase deficiency. Am J Cardiovasc Drugs. 2016;16(6):461-468. doi:10.1007/s40256-016-0203-2
  4. Malinová V, Balwani M, Sharma R, et al. Sebelipase alfa for lysosomal acid lipase deficiency: 5-year treatment experience from a phase 2 open-label extension study. Liver Int. 2020;40(9):2203-2214. doi:10.1111/liv.14603
  5. Vijay S, Brassier A, Ghosh A, et al. Long-term survival with sebelipase alfa enzyme replacement therapy in infants with rapidly progressive lysosomal acid lipase deficiency: final results from 2 open-label studies. Orphanet J Rare Dis. 2021;16(1):13. doi:10.1186/s13023-020-01577-4

Reviewed by Harshi Dhingra, MD, on 5/6/2022.